Safety and immunogenicity of a new formulation of interferon β-1a (Rebif® New Formulation) in a Phase IIIb study in patients with relapsing multiple sclerosis: 96-week results

Abstract

Background

A new formulation of subcutaneous (s.c.) interferon-β-1a has been developed (Rebif^® New Formulation, RNF), produced without fetal bovine serum and without human serum albumin as an excipient, with the aim of improving injection tolerability, and reducing immunogenicity.

Objectives

This article reports 96-week analyses of a Phase IIIb, open-label study of the safety and immunogenicity of RNF compared with historical (EVIDENCE study) and recent (REGARD study) data on the original formulation.

Methods

Patients with relapsing multiple sclerosis (McDonald criteria) and an Expanded Disability Status Scale score < 6.0 received RNF, 44 μg s.c. three times weekly.

Results

The proportion of neutralizing antibody-positive (NAb+) patients (serum NAb status ≥20 neutralizing units/mL) at week 96 (last observation carried forward; primary endpoint) was 17.4% (exact 95% confidence interval [CI]: 13.0–22.5), compared with 21.4% (95% CI: 17.2–26.2) in the EVIDENCE study, and 27.3% (95% CI: 22.8–32.1) in the REGARD study. The proportion of patients NAb+ at any time during the 96 weeks was 18.9% (95% CI: 14.4–24.2), compared with 27.1% (95% CI: 22.4–32.2) and 33.7% (95% CI: 28.9–38.7), respectively. Most pre-specified categories of adverse events were reported by patients in the RNF study at a similar or lower proportion than in the EVIDENCE and REGARD studies. Injection-site reactions were experienced by fewer patients than in the EVIDENCE and REGARD studies.

Conclusions

RNF has improved overall immunogenicity and safety profiles compared with the original formulation.

Keywords

immunogenicity injection-site reactions interferon-β-1a multiple sclerosis Rebif® New Formulation safety

Get full access to this article

View all access options for this article.

References

1 Durelli L Ricci A . Anti-interferon antibodies in multiple sclerosis. Molecular basis and their impact on clinical efficacy. Front Biosci 2004; 9: 2192–2204.

2 Ross C Clemmesen KM Svenson M . Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann Neurol 2000; 48: 706–712.

3 Goodin DS Frohman EM Hurwitz B . Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007; 68: 977–984.

4 Sorensen PS Ross C Clemmesen KM . Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003; 362: 1184–1191.

5 Sorensen PS Deisenhammer F Duda P . Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005; 12: 817–827.

6 Perini P Calabrese M Biasi G Gallo P . The clinical impact of interferon beta antibodies in relapsing-remitting MS. J Neurol 2004; 251: 305–309.

7 Petkau AJ White RA Ebers GC . Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler 2004; 10: 126–138.

8 Schellekens H . The immunogenicity of biopharmaceuticals. Neurology 2003; 61: S11–S12.

9 Schellekens H Casadevall N . Immunogenicity of recombinant human proteins: causes and consequences. J Neurol 2004; 251(Suppl. 2): II4–II9.

10.

10 Gottberg K Gardulf A Fredrikson S . Interferon-beta treatment for patients with multiple sclerosis: the patients' perceptions of the side-effects. Mult Scler 2000; 6: 349–354.

11.

11 Walther EU Hohlfeld R . Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology 1999; 53: 1622–1627.

12.

12 Giovannoni G Barbarash O Casset-Semanaz F . Immunogenicity and tolerability of an investigational formulation of interferon-beta1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis. Clin Ther 2007; 29: 1128–1145.

13.

13 Panitch H Goodin D Francis G . Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci 2005; 239: 67–74.

14.

14 Panitch H Goodin DS Francis G . Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology 2002; 59: 1496–1506.

15.

15 Mikol DD Barkhof F Chang P . Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 2008; in press.

16.

16 Mikol D Barkhof F Chang P . REGARD Study Group. The REGARD trial: a randomised assessor-blinded trial comparing interferon beta-1a and glatiramer acetate in relapsing-remitting multiple sclerosis. Mult Scler 2007; 13(Suppl. 2): 119.

17.

17 Kurtzke JF . Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444–1452.

18.

18 McDonald WI Compston A Edan G . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

19.

19 Francis GS Rice GP Alsop JC . Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology 2005; 65: 48–55.

20.

20 Gneiss C Reindl M Lutterotti A . Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity. Mult Scler 2004; 10: 507–510.

21.

21 Bellomi F Scagnolari C Tomassini V . Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years. J Neurol Sci 2003; 215: 3–8.

22.

22 Sorensen PS Koch-Henriksen N Bendtzen K . Are ex vivo neutralising antibodies against IFN-beta always detrimental to therapeutic efficacy in multiple sclerosis. Mult Scler 2007; 13: 616–621.

23.

23 Malucchi S Sala A Gilli F . Neutralizing antibodies reduce the efficacy of beta IFN during treatment of multiple sclerosis. Neurology 2004; 62: 2031–2037.

24.

24 Hartung HP Polman C Bertolotto A . Neutralising antibodies to interferon beta in multiple sclerosis: expert panel report. J Neurol 2007; 254: 827–837.

25.

25 Files JG Hargrove D Delute L Cantillon M . Measured neutralizing titers of IFN-beta neutralizing antibodies (NAbs) can depend on the preparations of IFN-beta used in the assay. J Interferon Cytokine Res 2007; 27: 637–642.

26.

26 Sominanda A Rot U Suoniemi M Deisenhammer F Hillert J Fogdell-Hahn A . Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity. Mult Scler 2007; 13: 208–214.

27.

27 Mohr DC Goodkin DE Likosky W . Therapeutic expectations of patients with multiple sclerosis upon initiating interferon beta-1b: relationship to adherence to treatment. Mult Scler 1996; 2: 222–226.

28.

28 Mohr DC Likosky W Boudewyn AC . Side effect profile and adherence to in the treatment of multiple sclerosis with interferon beta-1a. Mult Scler 1998; 4: 487–489.

29.

29 Jaber A Bozzato GB Vedrine L . A novel needle for subcutaneous injection of interferon β-1a: Effect on pain in volunteers and satisfaction in patients with multiple sclerosis. BMC Neurol 2008; in press.

30.

30 Brearley C Jaber A Bertolino M Priestley A Seiberling M . Assessment of the safety, tolerability, and PK/PD properties of two new formulations of subcutaneously administered IFN-beta1a: a double-blind, placebo-controlled comparison with the currently available formulation. Int J Clin Pharmacol Ther 2007; 45: 307–318.

31.

31 Mikol D Lopez-Bresnahan M Taraskiewicz S Chang P Rangnow J . A randomized, multicentre, open-label, parallel-group trial of the tolerability of interferon beta-1a (Rebif) administered by autoinjection or manual injection in relapsing-remitting multiple sclerosis. Mult Scler 2005; 11: 585–591.

32.

32 Phillips JT Rice G Frohman E . A multicenter, open-label, phase II study of the immunogenicity and safety of a new prefilled syringe (liquid) formulation of Avonex in patients with multiple sclerosis. Clin Ther 2004; 26: 511–521.

33.

33 Reess J Haas J Gabriel K Fuhlrott A Fiola M . Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy. Mult Scler 2002; 8: 15–18.